Adjuvant and Neoadjuvant Therapy for Gastric Cancer - BC Cancer ...

Peri-operative Treatment forGastric CancerHoward LimMedical OncologistB.C. Cancer Agency

Esophagus and Stomach

Question• Is there a preferred perioperativetreatment for patients with gastriccancer?

Surgery6

The Goal – R0 ResectionEsophagealSCC(%)EsophagealAdeno-CA(%)GastricAdeno-CA(%)pT1MucosaSubmucosa1009110010010098pT2848487pT3706860pT4485941Siewert et al. Ann Surg 1998; 228: 7 449-461Siewert et al. in Kelsen (Ed.) GI Oncology 2002; Table 18-3

Stomach Surgery - LymphadenectomyD1D2D3nodes adjacent to the stomach+ branches celiac axisnodes along the aorta

D1 versus D2 LymphadenectomyMorbidity 25% v 43%; P = .001Mortality 4% v 10%; P = .004Morbidity and mortality influenced- pancreatectomy- splenectomy- and ageHartgrink et al., J Clin Oncol 2004;22:2069-2077

D1 versus D2 LymphadenectomySubgroup with N2 diseaseHartgrink et al., J Clin Oncol 2004;22:2069-2077

D1 versus D3 Lymphadenectomy“D3 nodal dissection, compared with that of D1,offers a survival benefit for patients with gastric cancerwhen done by well trained, experienced surgeons.”Wu et al. Lancet Oncol 2006;7:309–15

BC ExperienceFigure 5 – Kaplan-Meier survival curves comparing margins

BC ExperienceFigure 3 – Kaplan-Meier survival curves comparing lymph node ratio. < 0.2 vs> 0.2

BC ExperienceFigure 4 – Kaplan-Meier survival curves comparing use of perioperativetreatment. a indicates chemotherapy +/- radiation, n indicates notreatment

Key to Gastric Cancer• Surgery is the key for curative intenttreatment• Chemotherapy and Radiation do notmake up for inadequate surgery• Peri-operative treatment still confers asurvival benefit16

Peri-operative chemotherapy17

UK MAGIC TrialSt. II + IIIGastric +Junction +EsophagusN = 5031994-2002RANDOMChemotherapy:ECF x 3 Resection ECF x 3Primary endpoint: 5-y-survivalSurgery alone*ECF: Epirubicin 50mg/m2 d1, Cisplatin 60mg/m2 d1, 5-FU 200mg/m2/d cont iv, qd 2218Cunningham D et al. N Engl J Med 2006;355:11-20

UK MAGIC TrialMaximalDiameterCTXSURG3 cm 5 cmP-value

Chemotherapy250 pts assigned to chemotherapy (86%completed all 3 cycles)209 pts underwent surgery137 pts proceeded to postopchemotherapy37 pts disease progression10 post-op complications11 pt choice2 lack of response9 Other104 pts completed post-opchemotherapy (41.6% of 250 ptsinitially assigned)- After surgery – no increase ingrade 3/4 toxicity22

Surgery Details• Chemotherapy group – 229 (91.6%) pts wentfor surgery• Surgery within 3-6 weeks of completion ofchemotherapy• Post-operative complications were similar(45.7% vs 45.3%; chemo vs. no chemo),number of deaths at 30 days (5.6% vs 5.9%)and median stay in hospital 13 days bothgroups.23

UK MAGIC Trial5-y-OS36%23%24Cunningham D et al. N Engl J Med 2006;355:11-20

France FNCC 94012 - FFCD 9703St. II + IIIGastric +Junction +N = 2241995-2003RANDOMChemotherapy:CF x 2 Resection CF x 4Primary endpoint: Survival20% 35% after 5 years, α=5%, β=20%Surgery alone*CF: Cisplatin 100mg/m2 d1, 5-FU 800mg/m2/d d1-5, qd 2825Boige, V. et al. ASCO 2007 #4510

France FNCC 94012 - FFCD 97031,000,800,600,40A risque0,200,00logrank : p = 0,0210 1 2 3 4 5 6 7111 79 53 38 27 16 13 7113 93 65 53 41 27 17 145-year-survival: 24% (16-33%) vs 38% (28-47%)26Boige, V. et al. ASCO 2007 #4510

Adjuvant Treatment27

Adjuvant Radiotherapy• Two early trials using radiation alone• Post-operative XRT vs. surgery alone 3yr OS 23 % vs 27 %• Intra-operative radiation vs surgery -Mean survival 26.9 months vs. 30.8month28 6

Adjuvant chemoradiationSWOG 9008 / INT 0116R0-resectedgastricRANDOMobservation5-FU/LV 5-FU/LV5adenocarcimoma5-FU/LVRadiation5-FU/LV x245 GyChemotherapyLeucovorin 20mg/m 2 d1-5, 5-FU 425mg/m 2 d1-5, qd28Modification cycle 2: leucovorin 20mg/m 2 d1-4, 5-FU 400mg/m 2 d1-4Modification cycle 3: leucovorin 20mg/m 2 d1-3, 5-FU 400mg/m 2 d1-3Macdonald et al., NEJM 2001; 345: 725-730

Surgical Details• Eligibility:– Curative intent en bloc resection of thetumor– Negative Margins– Recommended D2 – perigastric, celiac,splenic, hepaticoartery and cardial lymphnodes

Surgical Details• Of the 552 patients whose records werereviewed• D2 lymphadecotomy – 10% (52 pts)• D1 lymphadecotomy – 36% (199 pts)• D0 lymphadecotomy – 54%

Adjuvant chemoradiationSWOG 9008 / INT 0116Macdonald et al., NEJM 2001; 345: 725-730

Adjuvant chemoradiationSWOG 9008 / INT 0116Median OS:Chemo XRTSurgeryHR for death36 mos27 mos1.35 p=0.005Macdonald et al., NEJM 2001; 345: 725-730

Subset Analysis• At 10 ys f/u – HR 1.32 for OS and 1.51for DFS• Sex, race, T and N stage, D-level ofresection, tumor location, histology andMaruyama index• Chemoradiation benefitted all subsetsexcept women (HR 1.0) and diffusehistology (HR 0.97)ASCO 2009, Abstract 4515

Conclusions• ChemoXRT is recommended forresected gastric cancer• Majority of patients - D0/D1 surgery• Reflection of current practice• Sub group analysis did not reflect adifference between D0/D1/D2 resection• Small numbers37 15

Adjuvant S-1ATCS-GC studySt. II + IIID2-resectionR0n = 10592001-2004RANDOMchemotherapyS1: 1 yearPrimary endpoint: survivalHR 0.70; 〈=0.05; power = 80%observation*S1 (Tegafur, Gimeracil, Oteracil): 80mg/m² d1-28, qd 43Sakuramoto S et al. N Engl J Med 2007;357:1810-1820

The role of oral fluoropyrimidines: S-1New oral DPD-inhibiting fluoropyrimidin,developed by Taiho (Japan), consisting ofTegafur (FT), Gimeracil (CDHP) und Oteracil-Kalium (Oxo)in a molar ratio of 1 : 0.4 : 1++Tegafur (FT) Gimeracil (CDHP) Oteracil-K (Oxo)

The role of oral fluoropyrimidines: S-1Kubota T. Br J Cancer 2008; 98:1301.1304

Adjuvant S-1Relapse-free survivalOverall survivalHR = 0.62 (95% CI, 0.50 to 0.77)P

Adjuvant S-1Pattern of relapseSakuramoto S et al. N Engl J Med 2007;357:1810-1820

Conclusions• Adjuvant S1 improves OS by approx.10%• Majority of patients had D2 resection• May not be valid in D0/D1 resection• Asian vs. Western patients? - Severalstudies showing that there does notappear to be a genetic difference• When equivalent surgery performed -treatment outcomes similar• S1 not approved in Canada45 23

Adjuvant Chemotherapy• Meta-analyses: analyses: only borderline significance for adjuvant chemotherapy.• Single studies: virtually all negative.• Subgroup analyses: stronger trend towards better survival with chemotherapy cinlymph node + disease.Meta-analysesStudies(n)Patients(n)Odds ratio (CI)Hermans 1993 11 2096 0.88 (0.78-1.08)Earle 1999 13 1990 0.80 (0.66-0.97)Mari 2000 21 3658 0.82 (0.75-0.89)Janunger 2002 21 3962 0.84 (0.74-0.96)Lordick F & Siewert JR. Gastric Cancer 2005; 8: 78-85

• Individual patient-level meta-analysis• 17 trials – 3838 patients representing60% of targeted data• Median f/u 7 years

• Median OS 4.9 yearssurgery only vs 7.8years in the adjuvantchemotherapy 5FUbased chemotherapy• HR for OS 0.82 p

Peri-operative treatmentOutcomes

BC Experience• Gastric/GE junction patients should beevaluated for consideration of perioperativetreatment• If not deemed to be a candidate for preoperativetreatment – consider postoperativetreatment

Reasons for peri-operative• Significant benefit with 3 cycles of preoperativechemotherapy• Post-operative patients may not becandidates for adjuvant treatment• Neo-adjuvant therapy can downstage disease– aid with achieving R0 resection• May weed out the poor performing patients(patients who progress on neo-adjuvanttreatment – will surgery really salvage them?)

BC Experience• Post-operative options:– ChemoXRT preferred – if poorly tolerated –try to complete the ChemoXRT portion– If anastomosis high, may not be suitablefor XRT as field too large– Consider for adjuvant chemotherapy

Gastric Cancer Treatment SchemeECCSurgeryECCSurgery - D1 or D2 resection or >15 lymph nodesIf upfront surgery - bleeding, not eligible for chemotherapySurgeryChemoXRT - currently 5FUFuture - ECC/CP with XRT or ECC/CP aloneNot eligible for XRT - consider 5FU basedchemotherapy - ECC?55

Conclusions• All patients with localized/resectablegastric cancer should be referred preoperativelyfor consideration of perioperativetreatment• Surgical management should include aminimum of 15 lymph nodes or D1lymph node dissection56

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